公开(公告)号：EP1430123A2

公开(公告)日：2004-06-23

申请号：EP01935403.4

申请日：2001-05-14

申请人： The Johns Hopkins University ,  Morphotek Inc. ,  Nicolaides, Nicholas, C. ,  Sass, Philip, M. ,  Grasso, Luigi ,  Vogelstein, Bert ,  Kinzler, Kenneth

发明人： NICOLAIDES, Nicholas, C. ,  SASS, Philip, M. ,  GRASSO, Luigi ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth, W.

IPC分类号： C12N15/10 ,  C12N15/01 ,  C12Q1/68 ,  A01K67/027

摘要： PROBLEM TO BE SOLVED: To provide a method for rendering cells hypermutable, and hypermutable cell lines altered genetically and phenotypically.SOLUTION: The invention relates to use of dominant negative alleles of human mismatch repair genes to generate hypermutable cells and organisms; the use of introducing genes into cells and transgenic animals by which new cell lines and animal varieties with new and useful properties can be prepared more efficiently than by relying on the natural rate of mutation; and use of mutagens for enhancing a rate of further augmented mutation.

摘要翻译： 要解决的问题：提供一种使细胞变性可变的方法，以及基因和表型改变的超可变细胞系。解决方案：本发明涉及人错配修复基因的显性阴性等位基因用于产生超可变细胞和生物体; 将基因导入细胞和转基因动物中，通过其可以比通过依赖于自然的突变率更有效地制备具有新的和有用的性质的新的细胞系和动物品种; 并使用诱变剂提高进一步增强突变率。

公开(公告)号：EP1430123B1

公开(公告)日：2018-01-03

申请号：EP01935403.4

申请日：2001-05-14

申请人： The Johns Hopkins University ,  Morphotek, Inc. ,  Nicolaides, Nicholas, C. ,  Sass, Philip, M. ,  Grasso, Luigi ,  Vogelstein, Bert ,  Kinzler, Kenneth

发明人： NICOLAIDES, Nicholas, C. ,  SASS, Philip, M. ,  GRASSO, Luigi ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth, W.

IPC分类号： C12N15/10 ,  C12N15/01 ,  C12Q1/68 ,  A01K67/027 ,  C07K14/47

摘要： PROBLEM TO BE SOLVED: To provide a method for rendering cells hypermutable, and hypermutable cell lines altered genetically and phenotypically.SOLUTION: The invention relates to use of dominant negative alleles of human mismatch repair genes to generate hypermutable cells and organisms; the use of introducing genes into cells and transgenic animals by which new cell lines and animal varieties with new and useful properties can be prepared more efficiently than by relying on the natural rate of mutation; and use of mutagens for enhancing a rate of further augmented mutation.

公开(公告)号：EP1259628A1

公开(公告)日：2002-11-27

申请号：EP01911013.9

申请日：2001-02-21

申请人： The Johns Hopkins UNiversity School of Medicine ,  Nicolaides, Nicholas, C. ,  Sass, Philip, M. ,  Grasso, Luigi ,  Vogelstein, Bert ,  Kinzler, Kenneth

发明人： NICOLAIDES, Nicholas, C. ,  SASS, Philip, M. ,  GRASSO, Luigi ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth, W.

IPC分类号： C12N15/81 ,  C12N5/10 ,  C12N15/01

CPC分类号： C12N15/81

摘要： Yeast cells are mutagenized to obtain desirable mutants. Mutagenesis is mediated by a defective mismatch repair system which can be enhanced using conventional exogenously applied mutagens. Yeast cells with the defective mismatch repair system are hypermutable, but after selection of desired mutant yeast strains, they can be rendered genetically stable by restoring the mismatch repair system to proper functionality.

公开(公告)号：EP1259628B1

公开(公告)日：2007-01-17

申请号：EP01911013.9

申请日：2001-02-21

申请人： THE JOHNS HOPKINS UNIVERSITY ,  Morphotek, Inc.

发明人： NICOLAIDES, Nicholas, C. ,  SASS, Philip, M. ,  GRASSO, Luigi ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth, W.

IPC分类号： C12N15/81 ,  C12N5/10 ,  C12N15/01

CPC分类号： C12N15/81

摘要： Yeast cells are mutagenized to obtain desirable mutants. Mutagenesis is mediated by a defective mismatch repair system which can be enhanced using conventional exogenously applied mutagens. Yeast cells with the defective mismatch repair system are hypermutable, but after selection of desired mutant yeast strains, they can be rendered genetically stable by restoring the mismatch repair system to proper functionality.

公开(公告)号：EP1268765B1

公开(公告)日：2008-08-13

申请号：EP01907187.7

申请日：2001-02-12

申请人： THE JOHNS HOPKINS UNIVERSITY ,  Morphotek, Inc.

发明人： NICOLAIDES, Nicholas, C. ,  SASS, Philip, M. ,  GRASSO, Luigi ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth, W.

IPC分类号： C12N15/10 ,  C12N1/20

CPC分类号： C12N15/1024 ,  C12N15/01 ,  C12N15/102

摘要： Bacteria are manipulated to create desirable output traits using dominant negative alleles of mismatch repair proteins. Enhanced hypermutation is achieved by combination of mismatch repair deficinecy and exogenously applied mutagens. Stable bacteria containing desirable output traits are obtained by restoring mismatch reparir activity to the bacteria.

公开(公告)号：EP1268765A2

公开(公告)日：2003-01-02

申请号：EP01907187.7

申请日：2001-02-12

申请人： The Johns Hopkins University

发明人： NICOLAIDES, Nicholas, C. ,  SASS, Philip, M. ,  GRASSO, Luigi ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth, W.

IPC分类号： C12N15/10 ,  C12N1/20

CPC分类号： C12N15/1024 ,  C12N15/01 ,  C12N15/102

摘要： Bacteria are manipulated to create desirable output traits using dominant negative alleles of mismatch repair proteins. Enhanced hypermutation is achieved by combination of mismatch repair deficinecy and exogenously applied mutagens. Stable bacteria containing desirable output traits are obtained by restoring mismatch reparir activity to the bacteria.

公开(公告)号：EP1476577B1

公开(公告)日：2009-04-15

申请号：EP03733833.2

申请日：2003-02-21

申请人： Morphotek, Inc.

发明人： GRASSO, Luigi ,  NICOLAIDES, Nicholas, C. ,  SASS, Philip, M.

IPC分类号： C12Q1/68 ,  C12N15/85

CPC分类号： C12N15/1024 ,  C12N15/85 ,  C12N2830/42 ,  C12N2840/203

摘要： The present invention features mammalian expression vectors that are useful for controlling DNA hypermutability in mammalian cell as well as the encoding polynucleotide sequences of vector sequences. In related aspects the invention features expression vectors and host cells comprising such polynucleotides. In other related aspects, the invention features transgenic cells expressing a mutator gene to enhance genome-wide mutagenesis, due to, for example, the presence of an exogenous mutator-encoding polynucleotide sequence. Further, the invention provides methods for using vector sequences that can remove the expression of such gene to restore DNA stability in a host cell.

公开(公告)号：EP1363930B1

公开(公告)日：2006-08-16

申请号：EP00978578.3

申请日：2000-11-14

申请人： Morphotek Inc.

发明人： NICOLAIDES, Nicholas, C. ,  GRASSO, Luigi ,  SASS, Philip, M.

IPC分类号： C07K14/47 ,  A61K39/00 ,  C12N15/00 ,  C12N15/63 ,  C12N15/85

CPC分类号： C07K14/47 ,  A61K39/00 ,  C07K2319/00

摘要： Dominant negative alleles of human mismatch repair genes can be used to generate hypermutable cells and organisms. By introducing these genes into cells and transgenic animals, new cell lines animal varieties with novel and useful properties can be prepared more efficiently than by relying on the natural rate of mutation. These methods are useful for generating genetic diversity within genes encoding for therapeutic antigens to produce altered polypeptides with enhanced antigenic and immunogenic activity. Moreover, these methods are useful for generating effective vaccines.

公开(公告)号：EP1351565A1

公开(公告)日：2003-10-15

申请号：EP01901992.6

申请日：2001-01-15

申请人： Morphotek Inc.

发明人： NICOLAIDES, Nicholas, C. ,  GRASSO, Luigi ,  SASS, Philip, M.

IPC分类号： A01H1/06 ,  A61K31/7076 ,  A61K31/7088 ,  C12N1/00 ,  C12N5/00 ,  C12Q1/68

CPC分类号： C12N15/1024 ,  A01H3/04 ,  C12N15/01 ,  C12N15/8212 ,  G01N33/5014 ,  G01N33/5088

摘要： Dominant negative alleles of human mismatch repair genes can be used to generate hypermutable cells and organisms. By introducing these genes into cells and transgenic animals, new cell lines and animal varieties with novel and useful properties can be prepared more efficiently than by relying on the natural rate of mutation. Methods of generating mutations in genes of interest and of making various cells mismatch repari defective through the use of chemicals to block mismatch repari in in vivo are disclosed.

公开(公告)号：EP1551988B1

公开(公告)日：2010-11-24

申请号：EP03765839.0

申请日：2003-07-21

申请人： Morphotek, Inc.

发明人： GRASSO, Luigi ,  KLINE, J. Bradford ,  NICOLAIDES, Nicholas, C. ,  SASS, Philip, M.

IPC分类号： C12P21/00 ,  C12P21/04 ,  C12N15/00 ,  C12N15/63 ,  C12N15/87 ,  C12Q1/68 ,  C12Q1/70 ,  G01N33/53 ,  A61K48/00

CPC分类号： C12N15/1024 ,  C07K16/00 ,  C12N15/1034

摘要： The use of mismatch repair (MMR) defective antibody producer cells offers a method to generate subclone variants with elevated protein production such as antibodies. Using MMR defective cells and animals, new cell lines and animal varieties with novel and useful properties such as enhanced protein production can be generated more efficiently than by relying on the natural rate of mutation. These methods are useful for generating genetic diversity within host cells to alter endogenous genes that can yield increased titer levels of protein production. By employing this method, two genes were discovered whose suppressed expression is associated with enhanced antibody production. Suppressed expression of these genes by a variety of methods leads to increased antibody production for manufacturing as well as strategies for modulating antibody production in immunological disorders. Moreover, the suppression of these two genes in host cells can be useful for generating universal high titer protein production lines.